TY - JOUR
T1 - Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers
AU - Mohebati, Arash
AU - Milne, Ginger L.
AU - Zhou, Xi Kathy
AU - Duffield-Lillico, Anna J.
AU - Boyle, Jay O.
AU - Knutson, Allison
AU - Bosworth, Brian P.
AU - Kingsley, Philip J.
AU - Marnett, Lawrence J.
AU - Brown, Powel H.
AU - Akpa, Esther G.
AU - Szabo, Eva
AU - Dannenberg, Andrew J.
PY - 2013/7
Y1 - 2013/7
N2 - COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E 4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6±1 days on urinary PGE-Mand LTE4 levels in smokers. Treatment with zileuton led to an18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by61%in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P=0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.
AB - COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E 4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6±1 days on urinary PGE-Mand LTE4 levels in smokers. Treatment with zileuton led to an18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by61%in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P=0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.
UR - http://www.scopus.com/inward/record.url?scp=84880069914&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880069914&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-13-0083
DO - 10.1158/1940-6207.CAPR-13-0083
M3 - Article
C2 - 23682075
AN - SCOPUS:84880069914
SN - 1940-6207
VL - 6
SP - 646
EP - 655
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 7
ER -